PROJECT SUMMARY: Significance: Our tissues experience frequent damage from injuries, infections and disease. Many organs in the human body can undergo self-repair to restore their function after damage. This recovery is accomplished through the actions of adult stem cells, which generate new cells of diverse types to replace damaged material. The capacity of adult stem cells to repair tissues makes them an appealing target for the development of therapies to restore the health of tissues that have been impaired by injury or aging. However, much remains unknown about how stem cell progeny adopt appropriate cell fates to repopulate tissues. This Pathway to Independence Award proposal seeks to understand the mechanisms that generate specific cell types in regenerative mammalian tissues. Candidate and environment: The candidate for this Pathway to Independence Award, Dr. Kara McKinley, is committed to leading an independent research group at the interface of cell biology and regenerative medicine. Dr. McKinley was trained in cell biology and biochemistry in the laboratory of Dr. Iain Cheeseman at MIT, where she uncovered mechanisms required for the assembly and regulation of the cell division machinery. During her postdoctoral studies at UCSF in the laboratory of renowned cell biologist Dr. Ron Vale, she has developed approaches for long-term live imaging of organoids, which are ?mini-organ? culture systems that mimic the cellular composition, architecture and responses of organs outside of the body. As described in this proposal, she will apply her organoid imaging approaches, combined with the targeted application of defined signals, to understand how extrinsic cues alter cell identity in two highly regenerative tissues: the small intestine (Aim 1), and the uterine lining (endometrium; Aim 2). Career development: During the mentored period, the candidate will gain additional training in mouse genetics to translate her findings from in vitro organoid systems into in vivo contexts, and in reproductive biology to translate her approaches from small intestinal organoids to endometrial organoids. Combining studies of the small intestine and the endometrium presents a unique and powerful platform for her independent group to apply common tools and approaches to reveal unifying features of regeneration, as well as to identify key aspects of organ-specific physiology. The candidate will work with experts in mouse genetics and reproductive biology at UCSF to build the necessary scientific skills to propel her research in these two complementary models. She will also undertake a suite of training to support her professional development. The execution of this proposal will equip the candidate with a formidable skillset and a robust platform to launch her independent research program.